Inflammation is a complex biological process that occurs in response to stimuli including, for example, infection, damage to cells and/or tissue, irritants, etc. While inflammation is vital for healing and combating infection, abnormal or excessive inflammation can adversely affect the health, comfort and/or mobility of a subject.
Many people worldwide are affected by inflammatory diseases or disorders such as acute or chronic idiopathic inflammatory arthritis, psoriasis, chronic dermatosis, myositis, demyelinating diseases, chronic obstructive pulmonary disease (COPD)1 interstitial lung disease, glomerulonephritis, interstitial nephritis, chronic active hepatitis, Crohn's disease, ulcerative colitis, plaque formation in atherosclerosis, degenerative diseases of the joints or nervous system, or multiple sclerosis (MS). Populations are ageing and an increasing number of people require medication for age-related inflammatory diseases.
A wide range of anti-inflammatory agents are known including steroids (such as glucocorticoids). In many cases these drugs are not as effective at treating some inflammatory conditions and/or also associated with adverse side effects. Long term use of steroids gives rise to chronic side effects, including immunosuppression, tissue wasting and loss of bone density.
Another well-known class of anti-inflammatory pharmaceuticals is the non-steroidal anti-inflammatory drugs (NSAID). The primary mode of action of known NSAIDs is through inhibition of the COX enzyme, which results in the inhibition of prostaglandin synthesis.
The NSAIDs currently in the marketplace provide some alternative to steroid-based treatments. However, administration of NSAIDs can cause highly undesirable side effects such as gastro-intestinal bleeding, ulcers and renal disease. In certain cases, these drugs do not provide effective relief for some sufferers of inflammatory disease.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost and activation of latent tuberculosis. (Rheumatology, 2007, 46(5): 887-888, Clin. Infect. Dis., 39: 295-299 and Ann. Rheum. Dis., 64 (Suppl III): 86)
Some current anti-inflammatory agents have adverse side effects which include any one or more of gastrointestinal tract damage, renal damage, photosensitivity, hepatic stimulation, headaches, dizziness, Crushing's syndrome, hypertension, hypokalemia, hypernatremia, etc. Furthermore, due to adverse reactions some anti-inflammatory agents are not suitable for some subjects including, for example, pregnant subjects and subjects with an inflammatory bowel disease. Adverse side-effects of anti-inflammatory agents can result from topical, oral or other forms of administration. Due to the limitations of many current anti-inflammatory drugs, there is a continual need to develop new anti-inflammatory agents.
The discovery of indomethacin, ethodolac and tenidap, as potent anti-inflammatory agents, has led to the exploration of indole nucleus. Indole derivatives have been found to possess potent wide spectrum of biological activities especially antibacterial, antifungal, anti-inflammatory and analgesic. Further, it has been reported that substitution of different heterocyclic or aromatic moieties at 2 or 3-position of indole nucleus modulates the anti inflammatory activity of such substituted indole derivatives.
The natural product indole-3-carbinol (I3C; found in vegetables of the genus Brassica) is a promising inflammatory prevention or therapy agent. As an anti-inflammatory compound, I3C suppresses inflammation and decreases the production of inflammatory cytokines known to be involved in initiating the inflammatory cascade. Furthermore, I3C has been shown to prevent the initiation of inflammatory responses at a very early stage by acting directly at the molecular level. Indole-3-carbinol has emerged as a promising chemo preventive agent due to its in vivo efficacy in various animal models.
U.S. Pat. No. 8,153,680 discloses alkyl indole-3-carbinol derivatives which can treat different cancers, including but not limited to prostate cancer, breast cancer, leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, and renal cancer.
U.S. Pat. No. 7,807,705 also discloses novel indole-3-carbinol derived antitumor agents which exhibit unique ability to target multiple molecular defects clinically relevant to oncogenesis and tumor progression.
Weng et al discloses Indole-3-carbinol and its metabolite 3,3′-diindoylmethane (DIM) target multiple aspects of cancer cell cycle regulation and survival including Akt-NFκB signaling, caspase activation, cyclin-dependent kinase activities, estrogen metabolism, estrogen receptor signaling, endoplasmic reticulum stress, and BRCA gene expression (Cancer Lett. 2008 Apr. 18; 262(2): 153)
A major complication in interpreting the physiological results is that Indole-3-carbinol is extremely unstable in acidic solution and it does not completely survive exposure to gastric acid. Sensitive analytical methods reveal that Indole-3-carbinol is converted to several indole derivatives in acid conditions. It is converted into biologically active components such as its dimer 3,3′-diindolylmethane (DIM) and indolo[3,2-b]carbazole (ICZ) through an acid-catalyzed reaction occurring in the low-pH environment of the stomach. ICZ is also produced, presumably from the nutritive indole, tryptophan, as a metabolic product of intestinal bacteria.
Although indole-3-carbinols are potent anti-cancer agents which are having multiple side effects with respect to dosage and administration they also posses potent anti-inflammatory activity. The present study is directed to prepare novel stable indole-3-carbinol derivatives having anti-inflammatory activity which are stable in vitro and vivo conditions
The present invention is also directed to prepare novel stable indole-3-carbinol as a scaffold to carry out structural modifications in order to achieve anti-inflammatory agents that are distinct in comparison to native indole-3-carbinol and its metabolites.